Abstract
Background:
Transarterial chemoembolization (TACE) with drug-eluting beads (DEB) is a new treatment modality. Little is known about prognostic factors affecting survival after DEB TACE for patients with hepatocellular carcinoma (HCC).
Methods:
Patients who underwent TACE with doxorubicin DEB for unresectable HCC during 2006–2008 were studied. Survival was calculated from the day of first transcatheter therapy. Survival analysis was performed using Kaplan–Meier estimations. Survival curves were compared using the log-rank test.
Results:
Fifty patients underwent chemoembolization with doxorubicin DEB. They included 39 women and 11 men, with a median age of 57.5 years (range 28–91 years). Eighteen patients died during the study period and 32 remained alive. Overall survival rates at 6 months, 1 year and 2 years from the first administration of doxorubicin DEB TACE were 71%, 65% and 51%, respectively. Prognostic factors found to be significant on univariate analysis were Child–Pugh class, Okuda staging, bilirubin > 2 mg/dl, albumin < 3.0 g/dl, Model for End-stage Liver Disease (MELD) score, serum alphafetoprotein (AFP), Cancer of the Liver Italian Programme (CLIP) score, tumour satisfying Milan criteria, Eastern Cooperative Oncology Group (ECOG) performance status (PS) and Barcelona Clinic Liver Cancer (BCLC) staging.
Conclusions:
Child–Pugh class, Okuda staging, bilirubin > 2 mg/dl, albumin < 3 g/dl, MELD score, serum AFP, CLIP score, Milan criteria, ECOG PS and BCLC staging were found to be prognostic markers of survival after treatment with doxorubicin DEB TACE in patients with unresectable HCC.
Keywords: hepatocellular carcinoma, chemoembolization, prognosis, drug-eluting beads
Introduction
Hepatocellular carcinoma (HCC) is a lethal malignancy, the incidence of which has continually increased in the USA over the past two decades.1 Transplantation and resection are curative therapies for HCC. The majority of patients, however, are not eligible for surgery because of advanced tumour, multifocal disease or poor liver reserve.2 Conventional transarterial chemoembolization (TACE) has been used as palliative treatment for patients with HCC who are ineligible for resection or transplantation. The survival benefit of this treatment over supportive care has been shown by two prospective randomized controlled trials carried out in 2002 in patients with unresectable HCC.3,4
Drug-eluting beads (DEB), which can be loaded with doxorubicin, represent a novel drug delivery system for chemoembolization. A slow and sustained release of drug is expected after intra-arterial delivery of DEB. Clinical studies by Varela et al.5 and Malagari et al.6 have reported this new drug delivery method to be safe and efficacious in the treatment of HCC. DEB TACE has been proposed to have a better pharmacokinetic profile than conventional TACE and to result in decreased systemic adverse effects.7
Factors which predispose patients to develop hepatic failure and related complications after transarterial treatment are generally identified as exclusion criteria during patient selection. Large tumours, poor liver reserve and portal vein thrombosis (PVT) have been associated with poorer outcomes in patients treated with conventional chemoembolization.8–10 Because DEB TACE is a new treatment modality, little is known about prognostic factors affecting survival after DEB TACE in patients with HCC. The aim of this study was to identify prognostic factors which influence survival from the time of transcatheter therapy in patients with unresectable HCC treated with doxorubicin DEB chemoembolization.
Materials and methods
Patient selection
The study was approved by the local institutional review board. Consecutive patients with HCC who underwent chemoembolization with doxorubicin DEB at a single institution during a period of 3 years (January 2006 to December 2008) were reviewed. A prospective database for patients treated after July 2008 was used, and data were collected retrospectively from case records for patients treated between January 2006 and June 2008. Patients were excluded if they had: (i) undergone resection; (ii) undergone radiofrequency ablation; (iii) received conventional chemoembolization, bland embolization or radioembolization with yttrium 90 (Y-90); (iv) received therapy with more than one type of embolic agent, or (v) received systemic chemotherapy such as sorafenib (Nexavar; Bayer Corp., Pittsburgh, PA, USA).
The American Association for the Study of Liver Diseases (AASLD) guidelines11 were used to diagnose HCC. This diagnosis was made if dynamic computed tomography (CT) or magnetic resonance imaging (MRI) showed a mass with typical vascular pattern, arterial enhancement and portal venous ‘washout’. For lesions sized 1–2 cm, two different studies were used to detect a typical pattern; for nodules >2 cm in diameter, only one typical study was used. Lesions with doubtful or inconclusive features on imaging were biopsied.
Okuda staging, Cancer of the Liver Italian Programme (CLIP) score and the Barcelona Clinic Liver Cancer (BCLC) staging system (Tables 1–3) have been used to stage HCC.12–14 The Eastern Cooperative Oncology Group (ECOG) system has been used to grade performance status (PS).15
Table 1.
Okuda staging
| 0 points | 1 point | |
|---|---|---|
| Tumour size | <50% of liver | >50% of liver |
| Ascites | No | Yes |
| Albumin | >3.0 g/dl | <3.0 g/dl |
| Bilirubin | <3.0 mg/dl | >3.0 mg/dl |
Stage I = 0 points; Stage II = 1,2 points; Stage III = 3,4 points
Table 3.
Barcelona Clinic Liver Cancer (BCLC) staging
| Performance status | Tumour stage | Okuda stage | Liver function | |
|---|---|---|---|---|
| Stage A | ||||
| A1 | 0 | Single < 5 cm | I | No portal hypertension |
| A2 | 0 | Single < 5 cm | I | Portal hypertension, normal bilirubin |
| A3 | 0 | Single < 5 cm | I | Portal hypertension, elevated bilirubin |
| A4 | 0 | Up to 3, <3 cm | I–II | Child–Pugh class A–B |
| Stage B | 0 | Large multi-nodular | I–II | A–B |
| Stage C | 1–2 | Vascular invasion or extrahepatic disease | I–II | A–B |
| Stage D | 3–4 | Any | III | C |
Table 2.
Cancer of the Italian Liver Programme (CLIP) staging
| 0 points | 1 point | 2 points | |
|---|---|---|---|
| Child–Pugh class | A | B | C |
| Alphafetoprotein | <400 | ≥400 | |
| Portal vein thrombosis | Absent | Present | |
| Tumour | Single, <50% | Multiple, <50% | Multiple, >50% |
Early stage = 0 points; intermediate stage = 1–3 points; advanced stage = 4–6 points
Data collection
Demographic (age, gender, ethnicity), clinical (aetiology, complications), laboratory parameters (bilirubin, albumin, creatinine, international normalized ratio [INR], alphafetoprotein [AFP]) and imaging (number of lesions, distribution, size, PVT) data were collected from patient case records. All patients underwent CT or MRI within 1 month before the procedure to assess tumour burden and presence of PVT. Hepatocellular carcinoma with more than five discrete nodules was referred to as diffuse tumour. Mean tumour size was calculated by the sum of the longest diameter of all measurable tumours.
Procedure
The type of therapy patients received was determined in a multidisciplinary liver tumour conference. Transcatheter therapy was performed via femoral artery approach under moderate sedation. Coeliac and superior mesenteric arteriograms were obtained to assess the arterial anatomy of the liver, tumour vasculature and portal vein patency. The chemotherapeutic agents were infused into the hepatic artery supplying the tumour(s). Patients who underwent chemoembolization with doxorubicin DEB received 300–500 µm and 500–700 µm LC beads (Biocompatibles PLC, Farnham, UK) impregnated with 75 mg of doxorubicin in each vial, or 100–300 µm LC beads impregnated with 50 mg of doxorubicin in each vial. Subsegmental or segmental chemoembolization were performed whenever possible. Flow in main and branch arteries supplying tumours were kept patent to maintain access for potential subsequent interventions. All patients were kept under observation for a period of 24 h and analgesia was administered as necessary.
Follow-up
Follow-up cross-sectional imaging (contrast-enhanced CT or MRI) was performed 3–4 weeks after treatment. Further treatments were based on clinical evaluation, laboratory values and imaging response. Patients with progressive disease underwent repeat treatments with the same modality. Patients with stable disease were followed with cross-sectional imaging every 3 months.
Statistics
Survival time is defined as the time from the first doxorubicin DEB chemoembolization to the date of death. Survival analysis was performed using Kaplan–Meier estimation. In univariate analysis, survival estimates were compared with log-rank test in the Kaplan–Meier method. Multivariate analysis was not carried out as the small sample size and low number of events per variable in the study could potentially lead to inconclusive results. spss Graduate Version 16.0 (SPSS, Inc., Chicago, IL, USA) was used for all statistical computations.
Results
A total of 50 patients with HCC who underwent chemoembolization with doxorubicin DEB and satisfied the inclusion criteria were included in the study. They included 39 women and 11 men, with a median age of 57.5 years (range 28–91 years). Eighteen patients (36%) died during the study period. Demographic, clinical, laboratory, tumour staging and imaging characteristics are summarized in Table 4.
Table 4.
Demographic and clinical characteristics
| Patient characteristics | Category | n (%) |
|---|---|---|
| Age at diagnosis, years | Median (range) | 57.50 (28–91) |
| Gender | Male | 39 (78.0%) |
| Female | 11 (22.0%) | |
| Ethnicity | White | 37 (74.0%) |
| African-American | 6 (12.0%) | |
| Other | 7 (14.0%) | |
| Aetiology | HCV | 24 (48.0%) |
| HBV | 6 (12.0%) | |
| ALD | 7 (14.0%) | |
| Cryptogenic | 7 (14.0%) | |
| Others | 6 (12.0%) | |
| Child–Pugh class | A | 24 (48.0%) |
| B | 14 (28.0%) | |
| C | 12 (24.0%) | |
| MELD score | Median (range) | 11.0 (7–28) |
| Tumour characteristics | Uni-nodular | 26 (52.0%) |
| Multi-nodular (2–5 nodules) | 15 (30.0%) | |
| Diffuse (>5 nodules) | 9 (18.0%) | |
| Mean tumour size | 5.49 cm (1.0–20.7 cm) | |
| Portal vein thrombosis | 12 (24.0%) | |
| Satisfying Milan criteria | 31 (62.0%) | |
| Bilirubin, mg/dl | Median (range) | 1.6 (0.4–10.7) |
| Albumin, g/dl | Median (range) | 2.8 (1.8–5.0) |
| INR | Median (range) | 1.2 (0.9–1.9) |
| Creatinine, mg/dl | Median (range) | 1.0 (0.2–9.8) |
| AFP, ng/l | Median (range) | 43.7 (5–2400) |
| AFP | <400 ng/l | 43 (86.0%) |
| >400 ng/l | 7 (14.0%) | |
| ECOG PS | 0 | 33 (66.0%) |
| 1 | 15 (30.0%) | |
| 2 | 2 (4.0%) | |
| BCLC staging | Stage A | |
| A1 | 0 (0.0%) | |
| A2 | 7 (14.0%) | |
| A3 | 6 (12.0%) | |
| A4 | 2 (4.0%) | |
| Stage B | 9 (18.0%) | |
| Stage C | 8 (16.0%) | |
| Stage D | 18 (36.0%) | |
| CLIP staging | ||
| 0 | 7 (14.0%) | |
| 1 | 12 (24.0%) | |
| 2 | 10 (20.0%) | |
| 3 | 10 (20.0%) | |
| 4–6 | 11 (22.0%) | |
| Okuda staging | ||
| I | 24 (48.0%) | |
| II | 14 (28.0%) | |
| III | 12 (24.0%) |
HCV, hepatitis C virus; HBV, hepatitis B virus; ALD, alcoholic liver disease; MELD, Model of End-stage Liver Disease; INR, international normalized ratio; AFP, alphafetoprotein; ECOG, Eastern Cooperative Oncology Group; PS, performance status; BCLC, Barcelona Clinic Liver Cancer; CLIP, Cancer of the Liver Italian Programme
The median duration of follow-up was 359 days (range 33–984 days). Median survival could not be calculated because more than 50% of the patients were alive at the end of the study period. Overall survival rates at 6 months, 1 year and 2 years from the first administration of doxorubicin DEB were 71%, 65% and 51%, respectively.
Univariate analysis
Univariate analyses of patient- and tumour-related variables along with various prognostic scoring systems are given in Table 5. Prognostic factors found to be associated with survival on univariate analysis were Child–Pugh classes A and B, early Okuda stage, bilirubin < 2.0 mg/dl, albumin > 3.0 g/dl, low Model for End-stage Liver Disease (MELD) score, AFP < 400 ng/ml, CLIP score < 3, tumour within the Milan criteria, ECOG PS of 0 and early-intermediate BCLC stages. Age, gender, ethnicity, PVT, creatinine, INR and tumour size were not found to be significant prognostic factors.
Table 5.
Univariate analysis of prognostic factors
| Variable | Category | n (events) | 1 year | 2 years | HR (95% CI) | P-value |
|---|---|---|---|---|---|---|
| Age at diagnosis | <60 years | 27 (10) | 77% | 61% | 1.1 (0.4–3.6) | 0.819 |
| >60 years | 23 (8) | 74% | 55% | |||
| Gender | Male | 39 (12) | 64% | 52% | 1.3 (0.7–2.3) | 0.291 |
| Female | 11 (6) | 72% | 64% | |||
| Ethnicity | White | 37 (13) | 71% | 62% | 0.6 (0.2–2.1) | 0.372 |
| Non-White | 13 (5) | 83% | 63% | |||
| Child–Pugh class | A | 24 (6) | 82% | 73% | 6.1 (1.7–22.3) | 0.002 |
| B | 14 (4) | 75% | 58% | 1.3 (0.3–5.5) | ||
| C | 12 (8) | 50% | 0% | |||
| MELD score | <15 | 36 (10) | 75% | 67% | 1.1 (0.9–1.2) | 0.01 |
| >16 | 14 (8) | 57% | 29% | |||
| Okuda stage | I | 24 (3) | 90% | 67% | 6.6 (1.4–30.6) | 0.005 |
| II | 14 (9) | 67% | 24% | 5.2 (0.9–29.2) | ||
| III | 12 (6) | 48% | 0% | |||
| AFP | <400 ng/l | 43 (8) | 81% | 74% | 3.9 (1.4–11.2) | 0.005 |
| >400 ng/l | 7 (10) | 29% | 14% | |||
| Portal vein | Thrombosed | 12 (5) | 58% | 40% | 0.4 (0.1–1.1) | 0.128 |
| Patent | 38 (13) | 73% | 64% | |||
| Bilirubin | <2 mg/dl | 32 (9) | 81% | 73% | 2.8 (1.0–7.8) | 0.038 |
| >2 mg/dl | 18 (9) | 50% | 25% | |||
| Albumin | >3.0 g/dl | 19 (4) | 88% | 67% | 5.3 (1.1–23.6) | 0.015 |
| <3.0 g/dl | 31 (14) | 46% | 35% | |||
| Tumour burden | Uni-nodular | 26 (8) | 70% | 62% | 1.3 (0.7–2.6) | 0.100 |
| Multi-nodular | 15 (4) | 73% | 48% | 1.1 (0.6–2.1) | ||
| Diffuse | 9 (6) | 44% | 0% | |||
| Milan criteria | Within | 31 (10) | 76% | 58% | 0.35 (0.1–0.9) | 0.038 |
| Beyond | 19 (8) | 47% | 31% | |||
| CLIP score | <3 | 29 (5) | 89% | 70% | 7.3 (2.0–25.0) | <0.001 |
| ≥3 | 21 (13) | 35% | 23% | |||
| BCLC stage | Early-intermediate | 32 (8) | 73% | 62% | 3.9 (1.3–11.6) | 0.009 |
| Advanced | 18 (10) | 28% | 0% | |||
| ECOG PS | 0 | 33 (5) | 82% | 82% | 4.1 (2.0–8.3) | <0.001 |
| 1–2 | 17 (13) | 35% | 12% |
HR, hazard ratio; 95% CI, 95% confidence interval; MELD, Model of End-stage Liver Disease; AFP, alphafetoprotein; CLIP, Cancer of the Liver Italian Programme; BCLC, Barcelona Clinic Liver Cancer; ECOG, Eastern Cooperative Oncology Group; PS, performance status
Discussion
Chemoembolization with doxorubicin DEB is a novel drug delivery system which performs the dual function of vascular embolization and intra-tumour drug delivery. Studies by Varela et al. and Malagari et al. demonstrate that chemoembolization is an effective procedure with a favourable pharmacokinetic profile.5,6 Identifying the subset of patients with unresectable HCC, in whom doxorubicin DEB TACE can prolong survival, is critical to improving clinical outcome.
Univariate analysis in this study showed Child–Pugh class, Okuda staging, bilirubin > 2 mg/dl, albumin < 3.0 g/dl, MELD score, serum AFP, CLIP score, Milan criteria, ECOG PS and BCLC staging to be significant prognostic factors for survival. Most of the earlier studies investigating prognostic factors for transcatheter therapies have focused on conventional chemoembolization. Table 6 summarizes the various prognostic factors for survival in patients with unresectable HCC in some of the published studies.8,9,16–21 Child–Pugh score and tumour size and stage have been found to be significant predictors of survival after conventional chemoembolization in most studies.8,9,17 The results of the current study are comparable with those of conventional chemoembolization as both Child–Pugh score and tumour stage (as assessed by Okuda and BCLC staging) were found to be prognostic factors in this study. However, tumour size and PVT, which were among the prognostic factors for conventional chemoembolization, were not found to influence survival after treatment with DEB in the present study.
Table 6.
Prognostic factors for survival in different studies
| Study | Year | n | Treatment | Prognostic factors |
|---|---|---|---|---|
| Mondazzi et al.8 | 1994 | 84 | TACE | Age, total bilirubin, Child–Pugh score, tumour size, change in AFP |
| Livraghi et al.16 | 1995 | 746 | PEI | Child–Pugh score, tumour stage |
| Allgaier et al.17 | 1998 | 132 | TACE/PEI | Child–Pugh score, Okuda stage, PVT, AFP |
| Llado et al.9 | 2000 | 143 | TACE | Ascites, AFP, tumour size, Child–Pugh score, pattern of Lipiodol intake, PVT |
| El Khaddari et al.18 | 2002 | 72 | TACE | Child–Pugh score, interval between treatment |
| Grieco et al.19 | 2003 | 81 | TACE | PVT, bilirubin, AFP, tumour size, Okuda, CLIP, BCLC |
| Goin et al.20 | 2005 | 121 | Y-90 (Theraspheres) | Infiltrative tumour, AST/ALT > 5 ULN, tumour burden > 50%, albumin < 3.0 g/dl, bilirubin > 2 mg/dl |
| Sato et al.21 | 2008 | 229 | Y-90 (Theraspheres) | Cirrhosis, infiltrative HCC, PVT, AFP, tumour burden |
TACE, transarterial chemoembolization; PEI, percutaneous ethanol injection; AFP, alphafetoprotein; PVT, portal vein thrombosis; CLIP, Cancer of the Liver Italian Programme; BCLC, Barcelona Clinic Liver Cancer; Y-90, yttrium 90 radioembolization; HCC, hepatocellular carcinoma
Advanced tumour stage (tumour burden > 50% of liver), infiltrative type of tumour, poor liver function (bilirubin > 2.0 mg/dl; albumin < 3.0 g/dl; elevated AST/ALT), and presence of PVT were found to be prognostic factors for survival after treatment with Y-90 radioembolization.20,21 In the current study, elevated bilirubin and elevated AFP were found to be prognostic factors on univariate analysis. The BCLC staging takes serum AFP, bilirubin levels and PS into consideration, and BCLC stage was found to be a prognostic factor in this study. Several studies have shown that Child–Pugh classification is one of the most powerful predictors of survival after transarterial chemoembolization.9,17,18,22 Georgiades et al. compared the prognostic accuracy of 12 HCC tumour staging systems and found the Child–Pugh scoring system to be the most accurate for predicting survival after conventional chemoembolization.23 In the current study Child–Pugh class and MELD score were both found to be predictors of survival, with 1-year survival rates in Child–Pugh classes A, B and C of 82%, 75% and 50%, respectively. Unlike this study, most of the existing clinical studies on treatment with doxorubicin DEB TACE have excluded patients in advanced stages, such as those with PVT and those in Child–Pugh class C.5,24
The presence of PVT has traditionally been considered as a contraindication for transarterial therapy.9,10 However, it was not found to influence overall survival in the current study. Chung et al. and Lee et al. also demonstrated that PVT did not adversely affect survival after conventional chemoembolization if a proper technique was employed.25,26 During transcatheter therapy for patients with PVT, super-selective embolization techniques were used during this study, when feasible, which may partially explain the result.
The limitations of this study include its small number of patients and relatively short-term follow-up; thus the results must be taken as preliminary. Despite its limitations, the variables identified as prognostic factors are in concurrence with the risk factors for conventional chemoembolization. The results obtained in the study can be used as a guide to design further prospective studies.
Conclusions
Chemoembolization with doxorubicin DEB is a novel drug delivery system used as palliative treatment in patients with unresectable HCC. Appropriate patient selection remains the most important factor able to influence clinical outcome. Serum albumin level, bilirubin level, serum AFP, liver reserve (Child–Pugh class and MELD score), HCC staging (by Okuda staging, Milan criteria, CLIP score and BCLC staging) and PS as assessed by ECOG classification were found to be predictors of survival.
Conflicts of interest
None declared.
References
- 1.El-Serag HB, Rudolph KL. Hepatocellular carcinoma: epidemiology and molecular carcinogenesis. Gastroenterology. 2007;132:2557–2576. doi: 10.1053/j.gastro.2007.04.061. [DOI] [PubMed] [Google Scholar]
- 2.Kassahun WT, Fangmann J, Harms J, Hauss J, Bartels M. Liver resection and transplantation in the management of hepatocellular carcinoma: a review. Exp Clin Transplant. 2006;4:549–558. [PubMed] [Google Scholar]
- 3.Llovet JM, Real MI, Montana X, Planas R, Coll S, Aponte J, et al. Arterial embolization or chemoembolization versus symptomatic treatment in patients with unresectable hepatocellular carcinoma: a randomized controlled trial. Lancet. 2002;359:1734–1739. doi: 10.1016/S0140-6736(02)08649-X. [DOI] [PubMed] [Google Scholar]
- 4.Lo CM, Ngan H, Tso WK, Liu CL, Lam CM, Poon RT, et al. Randomized controlled trial of transarterial lipiodol chemoembolization for unresectable hepatocellular carcinoma. Hepatology. 2002;35:1164–1171. doi: 10.1053/jhep.2002.33156. [DOI] [PubMed] [Google Scholar]
- 5.Varela M, Real MI, Burrel M, Forner A, Sala M, Brunet M, et al. Chemoembolization of hepatocellular carcinoma with drug eluting beads: efficacy and doxorubicin pharmacokinetics. J Hepatol. 2007;46:474–481. doi: 10.1016/j.jhep.2006.10.020. [DOI] [PubMed] [Google Scholar]
- 6.Malagari K, Chatzimichael K, Alexopoulou E, Kelekis A, Hall B, Dourakis S, et al. Transarterial chemoembolization of unresectable hepatocellular carcinoma with drug eluting beads: results of an open-label study of 62 patients. Cardiovasc Intervent Radiol. 2008;31:269–280. doi: 10.1007/s00270-007-9226-z. [DOI] [PubMed] [Google Scholar]
- 7.Hong K, Khwaja A, Liapi E, Torbenson MS, Georgiades CS, Geschwind JF. New intra-arterial drug delivery system for the treatment of liver cancer: preclinical assessment in a rabbit model of liver cancer. Clin Cancer Res. 2006;12:2563–2567. doi: 10.1158/1078-0432.CCR-05-2225. [DOI] [PubMed] [Google Scholar]
- 8.Mondazzi L, Bottelli R, Brambilla G, Rampoldi A, Rezakovic I, Zavaglia C, et al. Transarterial oily chemoembolization for the treatment of hepatocellular carcinoma: a multivariate analysis of prognostic factors. Hepatology. 1994;19:1115–1123. [PubMed] [Google Scholar]
- 9.Llado L, Virgili J, Figueras J, Valls C, Dominguez J, Rafecas A, et al. A prognostic index of the survival of patients with unresectable hepatocellular carcinoma after transcatheter arterial chemoembolization. Cancer. 2000;88:50–57. doi: 10.1002/(sici)1097-0142(20000101)88:1<50::aid-cncr8>3.0.co;2-i. [DOI] [PubMed] [Google Scholar]
- 10.Ikeda K, Kumada H, Saitoh S, Arase Y, Chayama K. Effect of repeated transcatheter arterial embolization on the survival time in patients with hepatocellular carcinoma. An analysis by the Cox proportional hazard model. Cancer. 1991;68:2150–2154. doi: 10.1002/1097-0142(19911115)68:10<2150::aid-cncr2820681011>3.0.co;2-f. [DOI] [PubMed] [Google Scholar]
- 11.Murray KF, Carithers RL., Jr AASLD practice guidelines: evaluation of the patient for liver transplantation. Hepatology. 2005;41:1407–1432. doi: 10.1002/hep.20704. [DOI] [PubMed] [Google Scholar]
- 12.Okuda K, Ohtsuki T, Obata H, Tomimatsu M, Okazaki N, Hasegawa H, et al. Natural history of hepatocellular carcinoma and prognosis in relation to treatment. Study of 850 patients. Cancer. 1985;56:918–928. doi: 10.1002/1097-0142(19850815)56:4<918::aid-cncr2820560437>3.0.co;2-e. [DOI] [PubMed] [Google Scholar]
- 13.The Cancer of the Liver Italian Program (CCIP) Investigators. A new prognostic system for hepatocellular carcinoma: a retrospective study of 435. Hepatology. 1998;28:751–755. doi: 10.1002/hep.510280322. [DOI] [PubMed] [Google Scholar]
- 14.Llovet JM, Bru C, Bruix J. Prognosis of hepatocellular carcinoma: the BCLC staging classification. Semin Liver Dis. 1999;19:329–338. doi: 10.1055/s-2007-1007122. [DOI] [PubMed] [Google Scholar]
- 15.Oken MM, Creech RH, Tormey DC, Horton J, Davis TE, McFadden ET, et al. Toxicity and response criteria of the Eastern Cooperative Oncology Group. Am J Clin Oncol. 1982;5:649–655. [PubMed] [Google Scholar]
- 16.Livraghi T, Giorgio A, Marin G, Salmi A, de Sio I, Bolondi L, et al. Hepatocellular carcinoma and cirrhosis in 746 patients: longterm results of percutaneous ethanol injection. Radiology. 1995;197:101–108. doi: 10.1148/radiology.197.1.7568806. [DOI] [PubMed] [Google Scholar]
- 17.Allgaier HP, Deibert P, Olschewski M, Spamer C, Blum U, Gerok W, et al. Survival benefit of patients with inoperable hepatocellular carcinoma treated by a combination of transarterial chemoembolization and percutaneous ethanol injection – a single-centre analysis including 132 patients. Int J Cancer. 1998;79:601–605. doi: 10.1002/(sici)1097-0215(19981218)79:6<601::aid-ijc8>3.0.co;2-f. [DOI] [PubMed] [Google Scholar]
- 18.El Khaddari S, Gaudin JL, Abidi H, Picaud G, Rode A, Souquet JC. Chemoembolization in hepatocellular carcinoma: multivariate analysis of survival prognostic factors after the first session. Gastroenterol Clin Biol. 2002;26:728–734. [PubMed] [Google Scholar]
- 19.Grieco A, Pompili M, Caminiti G, Miele L, Covino M, Alfei B, et al. Prognostic factors for survival in patients with early-intermediate hepatocellular carcinoma undergoing non-surgical therapy: comparison of Okuda, CLIP, and BCLC staging systems in a single Italian centre. Gut. 2005;54:411–418. doi: 10.1136/gut.2004.048124. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 20.Goin JE, Salem R, Carr BI, Dancey JE, Soulen MC, Geschwind JF, et al. Treatment of unresectable hepatocellular carcinoma with intrahepatic yttrium 90 microspheres: a risk-stratification analysis. J Vasc Interv Radiol. 2005;16:195–203. doi: 10.1097/01.RVI.0000142602.79459.90. [DOI] [PubMed] [Google Scholar]
- 21.Sato KT, Ibrahim S, Lewandowski RJ, Ryu RK, Omary RA, Salem R. Abstract no. 34: analysis of variables affecting survival in patients with HCC treated with Y-90 radioembolization. J Vasc Interv Radiol. 2008;19:S14–S15. [Google Scholar]
- 22.Lu W, Li Y, He X, Chen Y. Transcatheter arterial chemoembolization for hepatocellular carcinoma in patients with cirrhosis: evaluation of two kinds of dosages of anticancer drugs and analysis of prognostic factors. Hepatogastroenterology. 2003;50:2079–2083. [PubMed] [Google Scholar]
- 23.Georgiades CS, Liapi E, Frangakis C, Park JU, Kim HW, Hong K, et al. Prognostic accuracy of 12 liver staging systems in patients with unresectable hepatocellular carcinoma treated with transarterial chemoembolization. J Vasc Interv Radiol. 2006;17:1619–1624. doi: 10.1097/01.RVI.0000236608.91960.34. [DOI] [PubMed] [Google Scholar]
- 24.Grosso M, Vignali C, Quaretti P, Nicolini A, Melchiorre F, Gallarato G, et al. Transarterial chemoembolization for hepatocellular carcinoma with drug-eluting microspheres: preliminary results from an Italian multicentre study. Cardiovasc Intervent Radiol. 2008;31:1141–1149. doi: 10.1007/s00270-008-9409-2. [DOI] [PubMed] [Google Scholar]
- 25.Chung J, Park J, Han J, Choi B, Han M. Hepatocellular carcinoma and portal vein invasion: results of treatment with transcatheter oily chemoembolization. Am J Roentgenol. 1995;165:315–321. doi: 10.2214/ajr.165.2.7618547. [DOI] [PubMed] [Google Scholar]
- 26.Lee HS, Kim JS, Choi IJ, Chung JW, Park JH, Kim CY. The safety and efficacy of transcatheter arterial chemoembolization in the treatment of patients with hepatocellular carcinoma and main portal vein obstruction. A prospective controlled study. Cancer. 1997;79:2087–2094. [PubMed] [Google Scholar]